Application of combination of FGF-2 (fibroblast growth factor 2) and kavazinin C in preparation of medicine for treating intrauterine adhesion

Abstract

The invention relates to the technical field of biological medicines, in particular to combined application of FGF-2 and kavazinin C in preparation of a medicine for treating intrauterine adhesion. The invention provides an application of combination of FGF-2 (fibroblast growth factor 2) and kavazinin C in preparation of a medicine for treating intrauterine adhesion. The gel prepared from the FGF-2 and the kavazinin C has an excellent treatment effect on intrauterine adhesion, and can efficiently repair the shape and the function of the damaged uterus and recover the pregnancy ability.

Description

Technical Field

[0001] The invention relates to the technical field of biomedicine, and in particular to application of FGF-2 and kava pepper C in combination in preparing a medicine for treating intrauterine adhesions. Background Art

[0002] In the past five years, the total number of artificial abortions has been hovering around 9.5 million cases per year, among which the incidence of intrauterine adhesions is as high as 30% to 40%, and the incidence rate is as high as 55% in 2022. In the past decade, the gold standard for the treatment of intrauterine adhesions in clinical practice has been hysteroscopic adhesion lysis, postoperative auxiliary hormone maintenance therapy or non-degradable balloons, contraceptive devices, anti-adhesion agents, etc. The quality of life of patients with mild intrauterine adhesions has been significantly improved, but for patients with moderate and severe intrauterine adhesions, the above standard treatment regimens have little effect, and the probability of re-adhesion after surgery is as high as 62.5%.

[0003] Due to the increase in intrauterine surgeries in clinical practice, intrauterine adhesions have become one of the main causes of secondary infertility. Among infertile women undergoing hysterosalpingography (HSG) evaluation, 1.5% suffer from this disease; among women with recurrent miscarriage, 5% to 39% suffer from this disease. Clinically, more than 48% of patients with intrauterine adhesions are diagnosed with moderate or severe intrauterine adhesions.

[0004] The existing treatment methods have unsatisfactory therapeutic effects and significant side effects. For example, hysteroscopic adhesion lysis has poor universality and is prone to postoperative complications such as cervical laceration, perforation, bleeding, infection, and cervical insufficiency due to the limitations of operation and equipment; there is currently no international unified standard for estrogen or progesterone treatment, and excessively high dosages will increase the possibility of side effects, and the body is very likely to develop tolerance; non-degradable balloons and contraceptive devices will cause pain and discomfort to patients, and patient compliance is poor; anti-adhesion agents, currently used in clinical practice, are relatively expensive and have average efficacy. Therefore, there is an urgent need for a uterine cavity treatment product that is highly efficient, has high patient compliance, and has high safety performance. Summary of the invention

[0005] The purpose of the present invention is to provide an application of FGF-2 and kava pepper C in the preparation of a drug for treating intrauterine adhesions.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides the application of FGF-2 and kava pepper C in the preparation of a medicine for treating intrauterine adhesions.

[0008] Preferably, the mass ratio of the FGF-2 to kava pepper C is 1-5:5-1.

[0009] The invention also provides a medicine for treating intrauterine adhesion, comprising FGF-2 and kava piperine C.

[0010] Preferably, the drug is in the form of tablets, capsules, powders, granules, creams, suppositories or gels.

[0011] The present invention also provides a method for preparing the medicine for treating intrauterine adhesions, wherein FGF-2, kava piperine C, a gel solution and a photoinitiator are mixed and solidified to obtain the medicine for treating intrauterine adhesions.

[0012] Preferably, the ratio of FGF-2 to gel solution is 0.5-1.5 mg: 0.09-1 mL;

[0013] Preferably, the ratio of kava pepper C to the gel solution is 0.5-1.5 mg: 0.09-1 mL.

[0014] Preferably, the mass ratio of the gel solution to the photoinitiator is 1:3-12.

[0015] Preferably, the gel solution is a methacrylylated hyaluronic acid hydrogel solution or a silk fibroin gel solution.

[0016] Preferably, the mass concentration of the gel solution is 0.8-1.2%.

[0017] Preferably, the curing method is: irradiating with 365nm ultraviolet light for 12 to 18s.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] Kava piperine C (FKC) used in the present invention is an active ingredient extracted from Pipermethysticum, which has a significant anti-inflammatory effect. Fibroblast growth factor FGFs has a total of 23 family members and is the largest subfamily of cell growth factors. Among them, basic fibroblast growth factor FGF2 is a recognized regeneration code and has achieved remarkable achievements in the field of wound repair. However, it is unknown whether FGF2 can have a relevant effect in the repair of endometrial wounds. The applicant found through preliminary literature research that FGF2 also has anti-inflammatory effects. In view of the problems of heterogeneous hyperplasia and strong inflammatory response of intrauterine adhesion wounds, we combine FGF2, FKC and hyaluronic acid HA through photocrosslinking technology to provide an FGF2 composite gel suitable for intrauterine adhesions. It was found through data verification that the gel prepared by FGF-2 and FKC in the present invention has excellent therapeutic effects on intrauterine adhesions, can efficiently repair the morphology and function of the damaged uterus, and restore the ability to conceive. In the composite gel prepared by the present invention, FGF2 plays a role in repairing the inner membrane and inhibiting scar hyperplasia, FKC plays an anti-inflammatory role, and hyaluronic acid or silk protein acts as a drug carrier and mechanical support-physical blocking role.

[0020] The synergistic effect between FGF2 and FKC of the present invention: excessive inflammatory response caused by intrauterine adhesions can lead to abnormal fibrosis and scar tissue formation. Especially in the process of wound healing, the continuous infiltration of inflammatory cells and the release of cytokines can stimulate the proliferation of fibroblasts and the excessive deposition of collagen, thereby leading to scar hyperplasia. Therefore, controlling the degree and duration of inflammatory response has an important auxiliary effect on strengthening FGF2 to promote endometrial remodeling.

[0021] FGF2 can stimulate the proliferation and migration of fibroblasts and keratinocytes, and accelerate the process of wound healing and scar repair. In this process, FGF2 can also regulate the expression of various cytokines, such as inhibiting the release of proinflammatory factors, reducing local inflammatory reactions, and thus reducing the adverse effects of inflammation; at the same time, FGF2 has a regulatory effect on the function of immune cells, can inhibit excessive immune responses, and reduce the risk of chronic inflammation. Therefore, the gel prepared by the method of the present invention can promote the repair of the endometrium, restore the shape and physiological function of the uterus, and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying creative work.

[0023] Figure 1 FGF2-FKC-HAMA gel has good physical properties and drug sustained-release performance. (A) Changes of elastic modulus G' and viscous modulus G" with frequency. (B) Changes of elastic modulus G' and viscous modulus G" with time. (C) Shear strain. (D) Changes of elastic modulus G' and viscous modulus G" with cycles. (E) Changes of the mass of the gel in PBS with time. (F) Changes of the mass of the gel at 37°C with time. (G) Changes of the concentration of FGF2 and FKC loaded in the gel in PBS with time.

[0024] Figure 2 The therapeutic effects of FKC-HAMA gel containing kava piperine and SAK-HAMA gel containing sakura glycosides on intrauterine adhesions. (A) Eosin-hematoxylin (H&E) staining experiment; (B) Quantitative analysis results.

[0025] Figure 3 FGF2-FKC-HAMA significantly improved the endometrial morphology of rats with intrauterine adhesions (the basic shape of the uterus of each group of rats was detected on the 14th day after surgery).

[0026] Figure 4 FGF2-FKC-HAMA can significantly alleviate the degree of uterine inflammation in rats with intrauterine adhesions. (A) Immunohistochemistry experiment; (B) Quantitative statistical graph of IL-6 expression; (C) Quantitative statistical graph of TNF-α expression.

[0027] Figure 5 After administration of FGF2-FKC-HAMA, the number of endometrial glands in rats with intrauterine adhesion increased, the degree of fibrosis decreased, and the endometrial morphology was significantly improved. H&E staining was used to detect the characteristic images of endometrial sections in rats in the control group, IUA model group, HAMA gel group, FKC-HAMA gel group, FGF2-HAMA gel group, and FGF2-FKC-HAMA gel group. Masson staining was used to detect the characteristic images of endometrial sections in rats in the control group, IUA model group, HAMA gel group, FKC-HAMA gel group, FGF2-HAMA gel group, and FGF2-FKC-HAMA gel group.

[0028] Figure 6The FGF2-FKC-HAMA gel has excellent biosafety. (A) The chicken embryo experiment detected the rupture of blood vessels in the chicken embryos induced by the control group, HAMA gel group, NaOH group, bFGF2-HAMA gel group, FKC-HAMA gel group, and bFGF2-FKC-HAMA gel group. (B) The hemolysis experiment detected the hemolysis of the following groups. The control group was added with 0.9% normal saline, and the others were added with HAMA gel, NaOH (1M), bFGF2-HAMA gel, FKC-HAMA gel, and bFGF2-FKC-HAMA gel to conduct hemolysis experiments and measure the corresponding hemolysis rates to obtain the hemolysis rates under different preparations. DETAILED DESCRIPTION

[0029] The present invention provides application of FGF-2 and kava pepper C in the preparation of a medicine for treating intrauterine adhesions.

[0030] In the present invention, the mass ratio of FGF-2 to kava piperine C is 1-5:5-1; preferably 2-4:5-1; more preferably 2-4:2-4; more preferably 1:1.

[0031] The invention also provides a medicine for treating intrauterine adhesion, comprising FGF-2 and kava piperine C.

[0032] In the present invention, the drug preparation types include tablets, capsules, powders, granules, creams, suppositories or gels; preferably gels.

[0033] The present invention also provides a method for preparing the medicine for treating intrauterine adhesions, wherein FGF-2, kava piperine C, a gel solution and a photoinitiator are mixed and solidified to obtain the medicine for treating intrauterine adhesions.

[0034] In the present invention, the ratio of FGF-2 to gel solution is 0.5-1.5 mg: 0.09-1 mL; preferably 0.7-1.3 mg: 1 mL; more preferably 0.9-1.1 mg: 1 mL; more preferably 1 mg: 1 mL.

[0035] In the present invention, the ratio of kava piperine C to the gel solution is 0.5-1.5 mg: 0.09-1 mL; preferably 0.7-1.3 mg: 1 mL; more preferably 0.9-1.1 mg: 1 mL; more preferably 1 mg: 1 mL.

[0036] In the present invention, the mass ratio of the gel solution to the photoinitiator is 1:3-12; preferably 1:9-11; and more preferably 1:10.

[0037] In the present invention, the gel solution is a methacryloyl hyaluronic acid hydrogel solution or a silk fibroin gel solution; preferably a methacryloyl hyaluronic acid hydrogel solution.

[0038] In the present invention, the mass concentration of the gel solution is 0.8-1.2%, preferably 0.9-1.1%, and more preferably 1%.

[0039] In the present invention, the curing method is: irradiating with 365nm ultraviolet light for 12 to 18 seconds, preferably 13 to 17 seconds, more preferably 14 to 16 seconds, and more preferably 15 seconds.

[0040] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0041] Example 1

[0042] (1) Preparation of methacryloyl hyaluronic acid (HAMA) gel: 1 g of hyaluronic acid was added to 100 mL of sterile triple distilled water, and after stirring to dissolve, 3 mL of methacrylic anhydride (MA) was first added, and the mixture was stirred and reacted at room temperature for 8 h, during which the pH of the solution was maintained at 8.5 with sodium hydroxide solution. After the reaction was completed, the solution was placed in a dialysis bag (8000-12000 Da) and dialyzed for 3 days, with the water changed 4 times a day. After the dialysis was completed, a HAMA solution was obtained, and the obtained HAMA solution was placed in an oven and concentrated to a concentration of 1.1%, which was the desired HAMA.

[0043] (2) 90 μL of 1.1% HAMA solution, 10 mg FGF2 solution and 30 mg kava piperine C were added to an EP tube, and 20 μL of photoinitiator LAP was added. After stirring and mixing, 396 nm ultraviolet light was used for 15 seconds to obtain FGF2-FKC-HAMA composite gel.

[0044] Example 2

[0045] Preparation of silk fibroin (SFMA) gel:

[0046] 1) Heat a beaker with 2L of water in an oil bath, add 4.24g of anhydrous sodium carbonate, stir and mix, weigh 2g of silk cocoons and cut them into small pieces. When the water temperature in the beaker rises to above 90℃, add the cut silk cocoons and continue heating for 1h, stirring from time to time.

[0047] 2) After heating, remove the beaker, filter out the silk fibroin (SF), and wash it with clean water. Repeat the operation in 1) for the filtered silk fibroin and filter and wash it. Then, heat the silk fibroin in 2L pure water at 100°C for 1h, wash it with pure water, and dry it.

[0048] 3) Weigh the dried silk to obtain 1.4 g, tear the silk into pieces and put it into a glass bottle, add 7 mL of pure water and 5.65 g of lithium bromide, and heat and dissolve it in a 65°C oil bath for 1 hour. After dissolution, filter it, add 700 μL of methyl methacrylic anhydride (GMA) to the filtered solution, and stir and react at 60°C for 3 hours. After the reaction is completed, dialyze for 3 days, and then dry and concentrate to obtain SFMA.

[0049] 4) FGF2 and kava pepper C (FKC) were mixed with 1% SFMA solution at a concentration of 1 mg / mL, and 4% LAP (photoinitiator) was added at a ratio of LAP:SFMA=1:10. After mixing, the mixture was irradiated with 365 nm ultraviolet light for 15 seconds to obtain FGF2-FKC-SFMA composite gel.

[0050] Experimental Example 1

[0051] Gel rheological properties test: The FGF2-FKC-HAMA composite gel (prepared in Example 1) was made into a cylindrical sample with a diameter of 8 mm and a height of 5 mm to evaluate its rheological properties. The sample was subjected to scanning tests of frequency, duration, strain and cycle on a rheometer. A vertebral plate with a diameter of 8 mm was selected for the experiment. The sample was placed on the platform and aligned with the vertebral plate. The temperature was kept constant at 25°C, and 0.1 to 100 rad s was performed at a fixed tension of 1%. -1 Dynamic frequency scanning in the range of 100s and dynamic time scanning in the range of 0 to 150s. At a frequency of 0.1Hz, the shear strain response rheological behavior of the hydrogel was studied, and the critical point of the gel state was obtained, and through the critical point, a dynamic cyclic scanning was obtained.

[0052] The results of rheological experiments showed that FGF2-FKC-HAMA was relatively stable under different pressures with time and frequency ( Figure 1 A and 1B), and has good self-healing ability under different pressures ( Figure 1 C and 1D). In addition, FGF2-FKC-HAMA has good swelling and anti-swelling properties, indicating that the gel has good water absorption properties ( Figure 1 E and 1F). Our drug sustained release experimental results confirmed that FGF2-FKC-HAMA has a sustained release effect on drugs. The sustained release time of FGF2 and FKC is as long as 24 hours, and the sustained release effect is excellent ( Figure 1 G). In summary, the obtained gel has good stability and self-healing properties, good water absorption performance, and excellent sustained-release effect.

[0053] Experimental Example 2

[0054] Construction and administration of rat endometrial injury and adhesion model: SPF female SD rats weighing 250-300g were taken, and the rat vaginal smears were observed daily. Female rats in estrus were selected for model construction. After the rats were anesthetized, the lower abdomen was disinfected, and the skin was cut 1 cm above the urethra to enter the abdominal cavity and expose the uterus. An incision was made at the Y-shaped uterine bifurcation, and the endometrium was scraped with a spatula to highly simulate the clinical intrauterine adhesion (IUA) induced by multiple abortions.

[0055] After curettage (i.e., after successful IUA modeling), the rats were divided into the following 6 groups (control group, modeling group, HAMA gel group (compared with Example 1, only FGF2 and kava piperine C were not added), FKC-HAMA gel group (compared with Example 1, only kava piperine C was not added), bFGF2-HAMA gel group (compared with Example 1, only kava piperine C was not added), bFGF2-FKC-HAMA gel group), and the composite gel containing various components was injected with a syringe (about 2 mL of gel can fill the uterus of one side of the rat). The wound was sutured under a sterile environment, and after the drug continued to act for 2 weeks, the rats died suddenly, and their uteri were taken for detection of various pathological and inflammatory indicators.

[0056] (1) Selection of Kava C (FKC)

[0057] In order to screen the natural product active ingredients with the best intrauterine therapeutic effect, we further determined the in vivo intrauterine adhesion therapeutic effects of two natural products, Kava piperine C (FKC) and Sakura sakura (SAK), obtained by high-throughput screening of in vitro anti-inflammatory activity. After the rat uterus was successfully constructed with intrauterine adhesion model (IUA) by curettage, it was divided into the following 5 groups (control group, modeling group, HAMA gel group, FKC-HAMA gel group, SAK-HAMA gel group (compared with Example 1, Kava piperine C was replaced with an equal amount of SAK)), and the composite gel containing various components was injected with a syringe (about 2 mL of gel can fill the unilateral rat uterus). After 2 weeks of gel treatment, the rats died suddenly, and their uteri were taken for H&E staining experiments, and the number of glands in the pathological sections was counted.

[0058] The experimental results are as follows Figure 2 As shown in A, the nucleus and cytoplasm of the uterine cavity tissue of the control group were evenly distributed, while the uterine cavity tissue of the model group showed severe nucleus and cytoplasm adhesion. The nucleus and cytoplasm adhesion of the HAMA gel treatment group was alleviated compared with the model group. The FKC-HAMA gel group was able to significantly alleviate the nucleus and cytoplasm adhesion, and basically restored it to the level of the control group, indicating that FKC has a good therapeutic effect on uterine cavity adhesion; however, the relief of nucleus and cytoplasm adhesion in the SAK-HAMA gel group was equivalent to that of the HAMA single-use group, indicating that SAK cannot effectively alleviate nucleus and cytoplasm adhesion. Further gland number statistics are shown in Figure 2 As shown in B: There were more glands on the slices in the control group, with nearly 18 glands per square centimeter of view, and the number of glands in the modeling group was significantly reduced, with only 3 glands per square centimeter of view; compared with the modeling group, HAMA gel alone could slightly increase the number of glands, but the effect was not weak; the FKC-HAMA gel treatment group could significantly increase the number of glands, basically restoring it to the level of the control group; however, the effect of the SAK-HAMA gel group on the glands was equivalent to that of the HAMA gel group, indicating that SAK could not increase the number of glands very well.

[0059] In summary, FKC is the best natural product active ingredient for preventing and treating intrauterine adhesions.

[0060] (2) In order to explore the therapeutic effect of FGF2-FKC-HAMA gel on intrauterine adhesion, we detected the recovery of rat uterus on the 14th day after surgery. The experimental results showed that the uterus of rats in the normal group was regular and full in shape, while the uterus of rats in the modeling group had severe adhesion and could not maintain a good full shape of the uterine cavity; although the adhesion of rat uterus in the HAMA gel treatment group and the FKC-HAMA gel treatment group was improved, there were still many local adhesions; the shape of rat uterus in the bFGF2-HAMA gel treatment group was better improved, and the shape of rat uterus in the bFGF2-FKC-HAMA gel treatment group was significantly better than that in the bFGF2-HAMA gel treatment group, and was basically no different from the normal group ( Figure 3 ).

[0061] (3) FGF2-FKC-HAMA gel significantly reduced the inflammatory response of the endometrium in rats with intrauterine adhesions

[0062] Since inflammatory response is the main cause of intrauterine adhesion formation and intrauterine re-adhesion, effective control of inflammatory response is of great significance for the treatment of intrauterine adhesion. Therefore, we investigated the degree of inflammation in each group of samples through immunohistochemistry and quantitative fluorescence PCR experiments. The experimental results showed that the degree of endometrial inflammation in rats with intrauterine adhesion was very high. HAMA gel alone could not effectively relieve endometrial inflammation. FKC and bFGF2 alone could relieve the degree of endometrial inflammation to a certain extent, but the relief effect was very limited; however, the combined use of FKC and bFGF2 could significantly relieve the degree of endometrial inflammation in rats, gradually returning it to normal levels ( Figure 4 ).

[0063] (4) FGF2-FKC-HAMA gel increased the number of endometrial glands and reduced the degree of fibrosis in rats with intrauterine adhesions

[0064] To explore the therapeutic effect of FGF2-FKC-HAMA gel on rat intrauterine adhesions, we observed the structural changes of the endometrium from a morphological perspective. The results of the hematoxylin and eosin (H&E) staining experiment showed that although the number of endometrial glands in the FGF2-HAMA gel and FKC-HAMA gel treatment groups was significantly less and the uterine thickness was still thinner compared with the normal group; however, compared with the IUA model group, the number of endometrial glands in the FGF2-HAMA and FKC-HAMA treatment groups increased significantly, and the endometrial thickness increased; however, the number of endometrial glands and endometrial thickness in the bFGF2-FKC-HAMA gel treatment group had returned to normal levels. Endometrial fibrosis is the main histopathological feature of the pathological progression of intrauterine adhesions. Therefore, we performed Masson staining on rat endometrial sections to evaluate the improvement of FGF2-FKC-HAMA gel on rat endometrial fibrosis. Masson staining results showed that compared with the IUA modeling group, the endometrial fibrosis in the FGF2-HAMA gel and FKC-HAMA gel treatment groups was reversed to a certain extent, and the degree of fibrosis decreased; the endometrial fibrosis in the bFGF2-FKC-HAMA gel treatment group was completely reversed to a level comparable to that of the normal group ( Figure 5 ).

[0065] Experimental Example 3

[0066] Since the biosafety of drugs is a key consideration in drug development. The chick chorioallantoic membrane (CAM) is a highly vascularized, non-nervated extraembryonic membrane. At the same time, the CAM is also a natural immune-deficient host. The CAM has a very long history of being used as an in vivo experimental platform for the assessment of drug safety. Therefore, we first investigated the biosafety of the prepared gel through a chicken embryo experiment. The specific experimental method is as follows: Buy breeding eggs from Taobao, put the breeding eggs in a 37℃ constant temperature incubator for 9 to 11 days, and then check them with a light bulb. After the inspection, draw the boundary of the air chamber, and mark it about 1mm above the edge of the air chamber junction and avoid the blood vessels. This is the injection point. Disinfect the area around the point with 2.5% iodine first, and then deiodinate with 75% alcohol. Use a punch to make a small hole at the injection point without damaging the shell membrane. Use a syringe to inject 0.2mL of each type of gel, then melt and seal it with paraffin, and place it back in a 37℃ constant temperature incubator for another 6 hours. Remove the paraffin and check the blood vessels. The specific gel groups were the control group added with 0.9% normal saline, and the others were HAMA gel group, NaOH group (concentration was 1 M), bFGF2-HAMA gel group, FKC-HAMA gel group, and bFGF2-FKC-HAMA gel group.

[0067] The results of the chicken embryo experiment showed that bFGF2-FKC-gel basically did not cause the capillaries of the chicken embryo to rupture ( Figure 6 A), indicating that it has very high biosafety. At the same time, the results of the hemolysis experiment showed that bFGF2-FKC-gel hardly causes hemolysis ( Figure 6 B). The above experimental results fully confirmed that bFGF2-FKC-gel has high biosafety.

[0068] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. The application of FGF-2 and kava pepper C in the preparation of drugs for the treatment of intrauterine adhesions.

2. The use according to claim 1, characterized in that: The mass ratio of the FGF-2 to kava pepper C is 1-5:5-1.

3. A drug for treating intrauterine adhesions, characterized in that: Includes FGF-2 and Kava C.

4. The drug according to claim 3, characterized in that The drug may be in the form of tablets, capsules, powders, granules, creams, suppositories or gels.

5. The method for preparing the drug for treating intrauterine adhesions according to claim 3 or 4, characterized in that: FGF-2, kava piperine C, gel solution and photoinitiator are mixed and solidified to obtain a medicine for treating intrauterine adhesions.

6. The preparation method according to claim 5, characterized in that: The ratio of the FGF-2 to the gel solution is 0.5-1.5 mg: 0.09-1 mL; the ratio of the kava pepper C to the gel solution is 0.5-1.5 mg: 0.09-1 mL.

7. The preparation method according to claim 5, characterized in that: The mass ratio of the gel solution to the photoinitiator is 1:3-12.

8. The preparation method according to claim 5, characterized in that: The gel solution is a methacrylylated hyaluronic acid hydrogel solution or a silk fibroin gel solution.

9. The preparation method according to claim 5, characterized in that: The mass concentration of the gel solution is 0.8-1.2%.

10. The preparation method according to claim 5, characterized in that: The curing method is: irradiating with 365nm ultraviolet light for 12 to 18 seconds.

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